One-Step Synthesis of [F]Aromatic Electrophile Prosthetic Groups via Organic Photoredox Catalysis.

To avoid the harsh conditions that are oftentimes adopted in direct radiofluorination reactions, conjugation of bioactive ligands with F-labeled prosthetic groups has become an important strategy to construct novel PET agents under mild conditions when the ligands are structurally sensitive. Prosthetic groups with [F]fluoroarene motifs are especially appealing because of their stability in physiological environments. However, their preparation can be intricate, often requiring multistep radiosynthesis with functional group conversions to prevent the decomposition of unprotected reactive prosthetic groups during the harsh radiofluorination.

First-in-Human Evaluation of [F]FDOPA Produced by Organo-Photoredox Reactions.

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans.

Synthesis of Cu-, Co-, and Ga-Labeled Radiopharmaceuticals Targeting Neurotensin Receptor-1 for Theranostics: Adjusting In Vivo Distribution Using Multiamine Macrocycles.

The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1-positive tumors.

Chelator boosted tumor-retention and pharmacokinetic properties: development of Cu labeled radiopharmaceuticals targeting neurotensin receptor.

Purpose: Accumulating evidence suggests that neurotensin (NTS) and neurotensin receptors (NTSRs) play key roles in lung cancer progression by triggering multiple oncogenic signaling pathways. This study aims to develop Cu-labeled neurotensin receptor 1 (NTSR1)-targeting agents with the potential for both imaging and therapeutic applications.

Method: A series of neurotensin receptor antagonists (NRAs) with variable propylamine (PA) linker length and different chelators were synthesized, including [Cu]Cu-CB-TE2A-iPA-NRA ([Cu]Cu-4a-c, i = 1, 2, 3), [Cu]Cu-NOTA-2PA-NRA ([Cu]Cu-4d), [Cu]Cu-DOTA-2PA-NRA ([Cu]Cu-4e, also known as [Cu]Cu-3BP-227), and [Cu]Cu-DOTA-VS-2PA-NRA ([Cu]Cu-4f).

Manufacturing 6-[F]Fluoro--DOPA via Flow Chemistry-Enhanced Photoredox Radiofluorination.

In this study, we introduce a practical methodology for the synthesis of PET probes by seamlessly combining flow chemistry with photoredox radiofluorination. The clinical PET tracer 6-[F]FDOPA was smoothly prepared in a 24.3% non-decay-corrected yield with over 99.

Radiolabeling Diaminosarcophagine with Cyclotron-Produced Cobalt-55 and [Co]Co-NT-Sarcage as a Proof of Concept in a Murine Xenograft Model.

Cobalt-sarcophagine complexes exhibit high kinetic inertness under various stringent conditions, but there is limited literature on radiolabeling and in vivo positron emission tomography (PET) imaging using no carrier added Co. To fill this gap, this study first investigates the radiolabeling of DiAmSar (DSar) with Co, followed by stability evaluation in human serum and EDTA, pharmacokinetics in mice, and a direct comparison with [Co]CoCl to assess differences in pharmacokinetics. Furthermore, the radiolabeling process was successfully used to generate the NTSR1-targeted PET agent [Co]Co-NT-Sarcage (a DSar-functionalized SR142948 derivative) and administered to HT29 tumor xenografted mice.

Development of F-Labeled hydrophilic -cyclooctene as a bioorthogonal tool for PET probe construction.

We report the development of a hydrophilic F-labeled a-TCO derivative [F]3 (log  = 0.28) through a readily available precursor and a single-step radiofluorination reaction (RCY up to 52%). We demonstrated that [F]3 can be used to construct not only multiple small molecule/peptide-based PET agents, but protein/diabody-based imaging probes in parallel.

Development of [F]F-5-OMe-Tryptophans through Photoredox Radiofluorination: A New Method to Access Tryptophan-Based PET Agents.

Although various radiolabeled tryptophan analogs have been developed to monitor tryptophan metabolism using positron emission tomography (PET) for various human diseases including melanoma and other cancers, their application can be limited due to the complicated synthesis process. In this study, we demonstrated that photoredox radiofluorination represents a simple method to access novel tryptophan-based PET agents. In brief, 4-F-5-OMe-tryptophans (l/d-T) and 6-F-5-OMe-tryptophans (l/d-T) were easily synthesized.

C, C and C-Cyanation of Electron-Rich Arenes via Organic Photoredox Catalysis.

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds.

Direct C-H Radiocyanation of Arenes via Organic Photoredox Catalysis.

Innovative labeling methods to incorporate the short-lived positron emitter carbon-11(C) into bioactive molecules are attractive for positron emission tomography (PET) tracer discovery. Herein, we report a direct C-H radiocyanation method that incorporates [C]cyanide (CN) to a series of functional electron-rich arenes via photoredox catalysis. This photoredox-mediated radiocyanation can proceed in an aerobic environment and is not moisture sensitive, which allows for ease of reaction setup and for scalable synthesis of C-aryl nitriles from readily available precursors.

Modular PET Agent Construction Strategy through Strain-Promoted Double-Click Reagent with Efficient Photoclick Step.

An efficient modular strategy for rapid assembly of positron emission tomography (PET) agents has been developed. The use of a sequential, rapid, and selective double-click reaction allows for a combinatorial approach to the cross-linking of positron emitter-bearing prosthetic groups with various ligands. The strain-promoted azide alkyne cyclization (SPAAC) coupling of F-labeled azide synthon with MC-DIBOD, a cyclooctadiyne with one of the triple bonds caged as a cyclopropenone moiety, produces a stable intermediate.

The Synthesis and Initial Evaluation of MerTK Targeted PET Agents.

MerTK (Mer tyrosine kinase), a receptor tyrosine kinase, is ectopically or aberrantly expressed in numerous human hematologic and solid malignancies. Although a variety of MerTK targeting therapies are being developed to enhance outcomes for patients with various cancers, the sensitivity of tumors to MerTK suppression may not be uniform due to the heterogeneity of solid tumors and different tumor stages. In this report, we develop a series of radiolabeled agents as potential MerTK PET (positron emission tomography) agents.

Biodistribution of Biomimetic Drug Carriers, Mononuclear Cells, and Extracellular Vesicles, in Nonhuman Primates.

Discovery of novel drug delivery systems to the brain remains a key task for successful treatment of neurodegenerative disorders. Herein, the biodistribution of immunocyte-based carriers, peripheral blood mononuclear cells (PBMCs), and monocyte-derived EVs are investigated in adult rhesus macaques using longitudinal PET/MRI imaging. Cu-labeled drug carriers are introduced via different routes of administration: intraperitoneal (IP), intravenous (IV), or intrathecal (IT) injection.

Development of F-Labeled Vinyl Sulfone-PSMAi Conjugates as New PET Agents for Prostate Cancer Imaging.

Radiolabeled prostate-specific membrane antigen (PSMA) ligands have been rapidly adopted as part of patient care for prostate cancer. In this study, a new series of F-labeled PSMA-targeting agents was developed based on the high-affinity Glu-ureido-Lys scaffold and F-vinyl sulfones (VSs), the tumor uptake and tumor/major organ contrast of which could be tuned by pharmacokinetic linkers within the molecules. In particular, F-PEG-VS-PSMAi showed the highest tumor uptake (12.

Arene radiofluorination enabled by photoredox-mediated halide interconversion.

Positron emission tomography (PET) is a powerful imaging technology that can visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates. The identification of new and improved molecular probes plays a critical role in PET, but its progress is somewhat limited due to the lack of efficient and simple labelling methods to modify biologically active small molecules and/or drugs. Current methods to radiofluorinate unactivated arenes are still relatively limited, especially in a simple and site-selective way.

Image-guided selection of Gd@C-dots as sensitizers to improve radiotherapy of non-small cell lung cancer.

Background: Recently, gadolinium-intercalated carbon dots (Gd@C-dots) have demonstrated potential advantages over traditional high-Z nanoparticles (HZNPs) as radiosensitizers due to their high stability, minimal metal leakage, and remarkable efficacy.

Results: In this work, two Gd@C-dots formulations were fabricated which bore carboxylic acid (CA-Gd@C-dots) or amino group (pPD-Gd@C-dots), respectively, on the carbon shell. While it is critical to develop innovative nanomateirals for cancer therapy, determining their tumor accumulation and retention is equally important.

Phototherapy and multimodal imaging of cancers based on perfluorocarbon nanomaterials.

Phototherapy, such as photodynamic therapy (PDT) and photothermal therapy (PTT), possesses unique characteristics of non-invasiveness and minimal side effects in cancer treatment, compared with conventional therapies. However, the ubiquitous tumor hypoxia microenvironments could severely reduce the efficacy of oxygen-consuming phototherapies. Perfluorocarbon (PFC) nanomaterials have shown great practical value in carrying and transporting oxygen, which makes them promising agents to overcome tumor hypoxia and extend reactive oxygen species (ROS) lifetime to improve the efficacy of phototherapy.

Development of Novel F-PET Agents for Tumor Hypoxia Imaging.

Tumor hypoxia is a major factor responsible for tumor progression, metastasis, invasion, and treatment resistance, leading to low local tumor control and recurrence after radiotherapy in cancers. Here,F-positron emission tomography (PET) probes are developed for visualizing viable hypoxic cells in biopsies. Pimonidazole derivatives and nitroimidazole-based agents bearing sulfonyl linkers were evaluated.

F- and F-Arene Deoxyfluorination via Organic Photoredox-Catalysed Polarity-Reversed Nucleophilic Aromatic Substitution.

Nucleophilic aromatic substitution (SAr) is routinely used to install F and F in aromatic molecules, but is typically limited to electron-deficient arenes due to kinetic barriers associated with C-F bond formation. Here we demonstrate that a polarity-reversed photoredox-catalysed arene deoxyfluorination operating via cation radical-accelerated nucleophilic aromatic substitution (CRA-SAr) enables the fluorination of electron-rich arenes with F and F under mild conditions, thus complementing the traditional arene polarity requirements necessary for SAr-based fluorination. The utility of our radiofluorination strategy is highlighted by short reaction times, compatibility with multiple nucleofuges, and high radiofluorination yields, especially that of an important cancer positron emission tomography (PET) agent [F]5-fluorouracil ([F]FU).

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids.

Background: Human immunodeficiency virus type-1 (HIV-1) and opiates cause long-term inflammatory insult to the central nervous system (CNS) and worsen disease progression and HIV-1-related neuropathology. The combination of these proinflammatory factors reflects a devastating problem as opioids have high abuse liability and continue to be prescribed for certain patients experiencing HIV-1-related pain.

Methods: Here, we examined the impact of chronic (3-month) HIV-1 transactivator of transcription (Tat) exposure to short-term (8-day), escalating morphine in HIV-1 Tat transgenic mice that express the HIV-1 Tat protein in a GFAP promoter-regulated, doxycycline (DOX)-inducible manner.

RXH-Reactive F-Vinyl Sulfones as Versatile Agents for PET Probe Construction.

Efficient radiolabeling reactions are important chemical tools in biomedical research especially in probe construction. Herein, three F-labeled vinyl sulfones were prepared. In particular, F-PEG1-VS (((2-(2-(fluoro-F)ethoxy)ethyl)sulfonyl)ethane) could not only allow chemoselective labeling of bioactive molecules containing -XH (X = S, NH) groups, but also react with red blood cells both and in living mice for potential cell tracking applications.